Upregulated UCA1 contributes to oxaliplatin resistance of hepatocellular carcinoma through inhibition of miR‐138‐5p and activation of AKT/mTOR signaling pathway

Hepatocellular carcinoma (HCC) inevitably developed oxaliplatin (OXA) resistance after long‐term treatment, but the mechanism remains unclear. Here, we found that LncRNA UCA1 was upregulated in most of OXA‐resistant HCC tissues and cells (HepG2/OXA and SMMC‐7721/OXA). Follow‐up analysis and online K...

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Published in:	Pharmacology research & perspectives Vol. 9; no. 1; pp. e00720 - n/a
Main Authors:	Huang, Guolin, Li, Li, Liang, Chaoyong, Yu, Fei, Teng, Cuifang, Pang, Yingxing, Wei, Tongtong, Song, Jinjing, Wang, Hanlin, Liao, Xiaoli, Li, Yongqiang, Yang, Jie
Format:	Journal Article
Language:	English
Published:	United States John Wiley & Sons, Inc 01-02-2021 John Wiley and Sons Inc Wiley
Subjects:	Animals Antineoplastic Agents - pharmacology Cancer therapies Carcinoma, Hepatocellular - genetics Carcinoma, Hepatocellular - metabolism Carcinoma, Hepatocellular - mortality Cell Line Chemotherapy Drug Resistance, Neoplasm - genetics Enrollments Gene expression Gene Expression Regulation, Neoplastic hepatocellular carcinoma Humans Kaplan-Meier Estimate Liver cancer Liver Neoplasms - genetics Liver Neoplasms - metabolism Liver Neoplasms - mortality long noncoding RNA Male Medical records Medical research Mice Mice, Inbred BALB C Mice, Nude MicroRNAs - antagonists & inhibitors miR‐138‐5p Mortality Original Oxaliplatin - pharmacology oxaliplatin resistance Pharmacology Proteins Proto-Oncogene Proteins c-akt - metabolism RNA, Long Noncoding - genetics RNA, Long Noncoding - metabolism Signal Transduction TOR Serine-Threonine Kinases - metabolism UCA1 Up-Regulation United States > US China long noncoding RNA UCA1 miR-138-5p oxaliplatin resistance hepatocellular carcinoma
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Summary:	Hepatocellular carcinoma (HCC) inevitably developed oxaliplatin (OXA) resistance after long‐term treatment, but the mechanism remains unclear. Here, we found that LncRNA UCA1 was upregulated in most of OXA‐resistant HCC tissues and cells (HepG2/OXA and SMMC‐7721/OXA). Follow‐up analysis and online Kaplan–Meier Plotter revealed that HCC patients with high UCA1 level had a shorter survival compared with those with low expression. Overexpression of UCA1 increased OXA IC50 in HepG2 and SMMC‐7721 cells, whereas knockdown of UCA1 decreased OXA IC50 in resistant counterparts. Moreover, dual luciferase reporter assay showed that co‐transfection of UCA1‐WT plasmid with miR‐138‐5p mimics enhanced fluorescence signals, whereas co‐transfection of UCA1‐Mut plasmid and miR‐138‐5p mimics did not induce any changes. Consistently, UCA1 levels in HepG2/OXA and SMMC‐7721/OXA cells were downregulated after transfected with miR‐138‐5p mimics. UCA1 silencing or transfection of miR‐138‐5p mmics inhibited the activation of AKT and mTOR in HepG2/OXA and SMMC‐7721/OXA cells, whereas UCA1 overexpression increased the phosphorylated AKT and mTOR levels in parental counterparts. Rapamycin or miR‐138‐5p mimics similarly suppressed the activation of AKT and mTOR, whereas UCA1 overexpression exert opposite roles. Interestingly, administration of rapamycin or miR‐138‐5p mimics apparently antagonized the effects of UCA1 on AKT and mTOR activation. Besides, depletion of UCA1 triggered more dramatic regression of HepG2 xenografts than that of HepG2/OXA xenografts with OXA treatment and impaired the p‐AKT and p‐mTOR levels in vivo. In conclusion, our findings provide the evidence that UCA1 may contribute to OXA resistance via miR‐138‐5p‐mediated AK /mTOR activation, suggesting that UCA1 is a potential therapeutic target for HCC.
Bibliography:	Funding information This study was funded by grants from the Natural Science Foundation of Guangxi Province (No. 2018GXNSFAA050053), the key planning development research program of Guangxi (grant no. guikeAB16380215), the Guangxi Natural Science Foundation (grant no. 2017GXNSFAA198103), and the Innovation Project of Guangxi Graduate Education (No. YCBZ2020054). Another three projects also funded this research, which was the first batch of cultivating talents of young and middle‐aged backbone teachers in Guangxi universities and Guangxi First‐class Discipline Project for Pharmaceutical Sciences (No. GXFCDP‐PS‐2018) and the Project of Innovation, Entrepreneurship, and Joint Training Base for Pharmaceutical Postgraduates. Guolin Huang, Li Li, Chaoyong Liang contributed equally. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2052-1707 2052-1707
DOI:	10.1002/prp2.720